Generic Levothyroxine Research Articles

Treating congenital hypothyroidism—which levothyroxine?

Biochemical screening of neonates for congenital hypothyroidism permits early initiation of levothyroxine treatment and thus prevents the development of intellectual disability. Two novel studies now address whether brand-name and generic levothyroxine are interchangeable in this context.

Generic Levothyroxine Compared With Synthroid in Young Children With Congenital Hypothyroidism

Clinicians who prescribe levothyroxine (LT4) for hypothyroidism often feel strongly about using a brand-name drug instead of a generic. The objective of the study was to determine whether Synthroid resulted in better control of congenital hypothyroidism than generic LT4. This was a 5-year retrospective study. The study was conducted at 1 tertiary care center. Children who were 0-36 months old with congenital hypothyroidism followed up at our center from 2006 to 2011 were treated with either Synthroid exclusively (35 subjects) or generic LT4 exclusively (27 subjects). We recorded the subjects' TSH and free T(4) measurements, how often their LT4 dose was adjusted, and the duration of follow-up. TSH variance between the groups was measured. Secondary end points were the frequency of LT4 dose changes and the variance in free T(4). Using the Wilcoxon rank sum test, there was no difference in TSH SD in the Synthroid group compared with the generic group (median 3.0 vs 2.2, P = .27). Using a linear mixed model, children treated with the generic LT4 had lower TSH estimated SD [1.35 with 95% confidence interval (CI) (1.194, 1.526)] than the Synthroid group [1.66 with 95% CI (1.536, 1.803)]. Similarly, no difference was observed in free T(4) SD between the groups using the Wilcoxon rank sum test (median 0.29 generic vs 0.36 Synthroid, P = .11), but the generic group had lower free T(4) estimated SD than the Synthroid group using the linear mixed model [0.216 with 95% CI (0.187, 0.249) vs 0.298 with 95% CI (0.273,0.326)]. Frequency of LT4 dosing adjustments was similar between the groups, both in total (median 2.0 for generic vs 3.0 for Synthroid, P = .097) and when adjusted for number of TSH checks (ratio 0.25 generic vs 0.31 Synthroid, P = .45). In our study of congenital hypothyroidism, generic LT4 treatment resulted in similar or better control of hypothyroidism compared with Synthroid, as assessed by the clinical outcomes of TSH variance and the frequency of LT4 dosing adjustments.

Generic drug discount programs: are prescriptions being submitted for pharmacy benefit adjudication?

In 2006, pharmacies began offering select generic prescription drugs at discount prices (e.g., $4 for a 30-day supply) through nonmembership and membership programs. As part of the contract in membership generic drug discount programs, the member agrees to forgo submission of the claim to the insurance company. Claims not submitted for insurance adjudication may result in incomplete pharmacy benefit manager (PBM) and health plan data, which could negatively influence adherence reporting and clinical programs. To address potentially missing claims data, the Centers for Medicare Medicaid Services (CMS) encourages Medicare Part D sponsors to incentivize network pharmacies to submit claims directly to the plan for drugs dispensed outside of a member's Part D benefit, unless a member refuses. The extent of PBM and health plan claims capture loss due to generic drug discount programs is unknown. To identify changes in levothyroxine utilizers' prescription claims capture rate following the advent of generic drug discount membership and nonmembership programs. This retrospective concurrent cohort study used claims data from 3.5 million commercially insured members enrolled in health plans located in the central and southern United States with Prime Therapeutics pharmacy benefit coverage. Members were required to be 18 years or older and younger than 60 years as of January 1, 2006, and continuously enrolled from January 1, 2006, through December 31, 2010. Members utilizing generic levothyroxine for at least 120 days during January 1, 2006, through June 30, 2006 (baseline period) from the same pharmacy group with supply on July 1, 2006, were placed into 1 of 3 pharmacy groups: (1) nonmembership (Walmart, Sam's Club, Target, Kroger, City Market, and King Soopers pharmacies), (2) membership (Walgreens, CVS, Albertsons, and Savon pharmacies), or (3) the reference group of all other pharmacies. The index date was defined as July 1, 2006. The levothyroxine claim providing supply on July 1, 2006, was the index claim. Members with a Kmart pharmacy index claim were excluded, since the Kmart membership drug discount program began prior to July 1, 2006. Levothyroxine claims capture nonpersistency, defined as the occurrence of a claim supply end date prior to a 180-day gap, was the primary outcome variable and was assessed from July 1, 2006, through June 30, 2010 (follow-up period). The odds of levothyroxine claims capture nonpersistency by pharmacy group were assessed using a logistic regression analysis adjusted for the following covariates: age, gender, median income in the ZIP code of residence (binomial for ≤ $50,000 vs. greater than $50,000), switch to a brand levothyroxine product during the follow-up period, index levothyroxine claim supply of 90 days or more, and index levothyroxine claim member cost share per 30-day supply in tertiles (≤ $5.00, $5.01-$7.99, ≥ $8.00). Of 2,632,855 eligible members aged 18 years or older, 13,427 met all study eligibility criteria. The baseline pharmacy groups were membership with 3,595 (26.8%), nonmembership with 1,919 (14.3%), and all other pharmacies with 7,913 (58.9%) members. The rates of levothyroxine claims capture persistency throughout the 4-year follow-up period were 85.4% for nonmembership (P = 0.593 vs. all other pharmacies), 77.7% for the membership group (P less than 0.001 vs. all other pharmacies), and 85.9% for all other pharmacies. The Kaplan-Meier comparison of claims capture persistency found nearly identical claims capture loss for the nonmembership compared with all other pharmacies group, and when compared in a multivariate logistic regression model, there was no difference in the odds of levothyroxine claims capture over 4 years follow-up (OR = 1.01, 95% CI = 0.88-1.16, P = 0.900). The membership generic drug discount programs (Walgreens, CVS, Alberstons, and Savon pharmacies) had a statistically significant 61% higher odds (OR = 1.61, 95% CI = 1.45-1.79, P less than 0.001) of levothyroxine claims capture nonpersistency. The onset of the difference between the membership group and the all other pharmacies group was temporally associated with the launch of the membership programs. In comparison to index levothyroxine member cost of ≤ $5.00 per 30-day supply, higher cost shares were associated with higher levothyroxine claims capture nonpersistency ($5.01 to $7.99 OR 1.34, 95% CI 1.19-1.52 and ≥ $8.00 OR 1.60, 95% CI 1.40-1.82). Among levothyroxine utilizers in 2006 (prior to the advent of drug discount programs), those with claims from a pharmacy that subsequently implemented a nonmembership generic drug discount program did not appear to have a different rate of levothyroxine claims capture than members from the reference group when followed through June 2010. Utilizers with claims from a pharmacy that subsequently implemented a membership program had a significantly lower levothyroxine claims capture rate. Increasing index levothyroxine member cost was associated with higher levothyroxine claims capture loss. Because the analysis could not directly measure claims capture loss associated with members who switched to a new pharmacy group without presenting their insurance information (e.g., membership discount programs), further research is needed to confirm these findings.

A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry

Levothyroxine (T4) is a narrow therapeutic index drug with classic bioequivalence problem between various available products. Dissolution of a drug is a crucial step in its oral absorption and bioavailability. The dissolution of T4 from three commercial solid oral dosage forms: Synthroid ® (SYN), generic levothyroxine sodium by Sandoz Inc. (GEN) and Tirosint ® (TIR) was studied using a sensitive ICP-MS assay. All the three products showed variable and pH-dependent dissolution behaviors. The absence of surfactant from the dissolution media decreased the percent T4 dissolved for all the three products by 26–95% (at 30 min). SYN dissolution showed the most pH dependency, whereas GEN and TIR showed the fastest and highest dissolution, respectively. TIR was the most consistent one, and was minimally affected by pH and/or by the presence of surfactant. Furthermore, dissolution of T4 decreased considerably with increase in the pH, which suggests a possible physical interaction in patients concurrently on T4 and gastric pH altering drugs, such as proton pump inhibitors. Variable dissolution of T4 products can, therefore, impact the oral absorption and bioavailability of T4 and may result in bioequivalence problems between various available products.

Generic Levothyroxine: What is all the Fuss About?

Generic Levothyroxine: What is all the Fuss About?

Bioequivalence of Generic and Brand-name Levothyroxine Products in the Treatment of Hypothyroidism

To compare relative bioavailability of Synthroid, Levoxine (Levoxine has been renamed Levoxyl), and 2 generic levothyroxine sodium preparations. Single-blind (primary investigators blinded), randomized, 4-way crossover trial. Ambulatory care. Twenty-two women with hypothyroidism who were clinically and chemically euthyroid and were receiving levothyroxine sodium, 0.1 or 0.15 mg. All patients received each of the 4 levothyroxine products for 6-week periods in the same dosage as their prestudy regimen with no washout period. The order of the drug sequences was randomly determined before study initiation. Area under the curve, time to peak serum concentrations, and peak serum concentrations of thyroxine, triiodothyronine, and free thyroxine index for all 4 products. All data analyses were completed prior to unblinding of the product codes. No significant differences between the 4 products were found in area under the curve or peak serum concentrations of total thyroxine, total triiodothyronine, or free thyroxine index. Although Synthroid produced a more rapid rise in total serum triiodothyronine concentration and a higher total peak serum triiodothyronine concentration than the other products, these differences were not statistically significant (P=.08). The Food and Drug Administration criterion for relative bioequivalence within 90% confidence intervals (0.8-1.25) was demonstrated (P<.05) for all pairs of products. Relative bioequivalence of 0.95 to 1.07 was demonstrated, tighter than the current bioequivalence criterion for oral formulations. The 4 generic and brand-name levothyroxine preparations studied are different but are bioequivalent by current Food and Drug Administration criteria and are interchangeable in the majority of patients receiving thyroxine replacement therapy. Further investigation is required to determine whether our results are equally applicable to all existing levothyroxine preparations.

Drug Substitution Encouraged by Law

To the Editor.— We have previously cautioned that generic levothyroxine sodium tablets are not always equivalent to a brand name product. We stressed that until such time that levothyroxine products become more uniform, physicians, pharmacists, and legislators should not encourage product switching (1980;244:1704). We suspect that other generic drugs may also not always be equivalent to brand name products. Current regulatory agencies seem unable to monitor adequately and ensure uniformity of the vast number of generic drugs. 1981 state of Michigan fiscal appropriation bill for social services provides a Medicaid pharmaceutical dispensing fee of $2.65 when a generic drug is dispensed and $2.15 when a brand name drug is dispensed. A 50-cent copayment per prescription is required from Medicaid patients older than 21 years when some brand name drugs are dispensed where generic equivalents are available. The copayment may be requested by the pharmacy before filling the prescription and,

Potency of brand name and generic levothyroxine

The tablet thyroxine content of a brand name and two generic products were studied. The mean thyroxine content was significantly different in the generic tablets when compared with that in the brand name product. The coefficient of variation of tablet thyroxine was lowest in the brand name, although this product had only 78% of expected potency. When these products were tested in three hypothyroid patients, two serum free thyroxine indexes were well outside the normal range when the most potent generic product was substituted for the brand name drug. Manufacturers should be required to measure the thyroxine content of their tablets. Until such time that levothyroxine products become more uniform, physicians, pharmacists, and legislators should not encourage product switching.

Potency of Brand Name and Generic Levothyroxine Products

The tablet thyroxine content of a brand name and two generic products were studied. The mean thyroxine content was significantly different in the generic tablets when compared with that in the brand name product. The coefficient of variation of tablet thyroxine was lowest in the brand name, although this product had only 78% of expected potency. When these products were tested in three hypothyroid patients, two serum free thyroxine indexes were well outside the normal range when the most potent generic product was substituted for the brand name drug. Manufacturers should be required to measure the thyroxine content of their tablets. Until such time that levothyroxine products become more uniform, physicians, pharmacists, and legislators should not encourage product switching. (<i>JAMA</i>244:1704-1705, 1980)

Substitution of Levothyroxine Products

ABSTRACT To the Editor.— Since calling attention to the problem of generic substitution of levothyroxine products in a recent letter (240:1241, 1978), we recently encountered evidence demonstrating that in one case, a generic product was not equal in potency to the brand name product.A 68-year-old woman who had primary hypothyroidism and a large goiter returned for a routine examination. Instead of receiving the brand name levothyroxine product we prescribed, the pharmacist had switched the prescribed drug to a look-alike generic product. While she was receiving 0.1 mg daily of generic levothyroxine, the patient's free thyroxine index was 1.0 (normal, 1.4 to 4.0), and by radioimmunoassay, the serum thyroid-stimulating hormone level was 76.0 μunits/mL (normal, less than 10). The drug regimen was changed to 0.1 mg daily of the brand name levothyroxine product, and seven weeks later, the free thyroxine index was 2.1, and the serum thyroidstimulating hormone level was 8.6

FILARIA LOA

In todays cost-conscious health care system, generic preparations should be prescribed whenever possible provided that safety and efficacy are not compromised. Several reports, however, suggest that generic levothyroxine may not always be interchangeable with the proprietary preparations. Such interchangeability is critical because patients are likely to receive different brands of levothyroxine during the life of their treatment. We report a case of severe hypothyroidism that developed in a patient who had been well controlled before receiving a generic levothyroxine preparation. Analysis of the patient9s tablet by high-pressure liquid chromatography showed that the levothyroxine content was approximately 30 percent less than its labeled content and outside current Food and Drug Administration (FDA) requirements. It is likely that poor tablet bioavailability was a contributory factor. Euthyroidism was achieved with the same dose of a more potent and possibly more bioavailable brand-name product. Until levothyroxine products become more uniform and the FDA confers therapeutic equivalence, product substitution with expense as the principal consideration should be avoided.